A substantial portion of our effort is directed towards the improvement of the known nucleosidic antimetabolites, 1-beta-D- arabinosylcytosine and 5-fluorodeoxyuridine with particular regard to overcoming the resistance to these drugs. Our strategy calls for the introduction of precursors into the cells from which the 5'-nucleotides could be released, and thus, the need for nucleoside kinase action could be circumvented. Three classes of compounds appear to be suitable for achieving this goal: 1) 5'-alkyl phosphates of 02:2'-cyclocytidine and 2) poly ara-C would be precursors of 5'-ara-CMP, 3) trinucleoside monophosphates could be a source of three different nucleotide analogs. Monomeric and polymeric phosphotriesters formed from oligodeoxyribonucleotides have a great promise as novel drugs. Due to their bindings to the complementary sequence of DNA or RNA, they could become stable gene-specific repressors. The biological activity of these compounds in the sensitive and resistant cell lines in tissue culture and in mice will be investigated. The metabolism of a few prototypes will be investigated. Their possible inhibitory action on selected enzymes, DNA polymerase, ribonucleotide reductase and nucleases will be studied.